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Stem Cells in cardiovascular diseases

Stem Cells in cardiovascular diseases. Arshed A. Quyyumi MD; FRCP Professor of Medicine Division of Cardiology Emory University School of Medicine. Atlanta, Georgia, USA. Disclosure of Financial Relationships.

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Stem Cells in cardiovascular diseases

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  1. Stem Cells in cardiovascular diseases Arshed A. Quyyumi MD; FRCP Professor of Medicine Division of CardiologyEmory University School of Medicine Atlanta, Georgia, USA

  2. Disclosure of Financial Relationships • Grant/research support: National Institutes of Health, American Heart Association Eli Lilly, Novartis, Pfizer, Amorcyte, Biomarin, Forest • Advisory Boards: Amorcyte, Endothelix, Novartis

  3. Types of Stem Cells • Embryonic stem cells – Pluripotent • Fetal and adult stem cells (e.g. mesenchymal cells) – Multipotent; capable of producing a small range of differentiated cell lineages appropriate to their location • Adult progenitor cells (e.g. skeletal myoblasts and endothelial progenitor cells) – Unipotent; has the least differentiation potential • Induced pluripotent stem cells (IPS)

  4. Endothelial Progenitor Cells Blood cells Hematopoeitic cells Stromal or Mesenchymal MAPC Osteocytes, Chondrocytes Myocytes (Skeletal) (Cardiac) Adult Bone Marrow Stem Cell Plasticity Neural cells Epidermal cells Ectodermal Progenitor Cells Mesodermal Progenitor Cells Bone Marrow Stem Cells Endodermal Progenitor Cells Hepatocytes Resident stem cells: Heart, skeletal muscle, Adipose tissue, brain, Lung etc.

  5. Endothelial cells VEGF Hypoxia HIF-1 SDF-1 PDGF Smooth muscle cells CXCR4 Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003) Cerdani DJ Nat Med 2004

  6. Human studies with cell therapy in cardiovascular diseases • Cell types: • Endothelial progenitor cells: • Bone marrow mononuclear cells, • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc • Peripheral blood progenitors (ex vivo expansion) • Cord blood • Skeletal myoblasts • Mesenchymal stem cells • Resident cardiac stem cells • Adipose tissue progenitors • Disease states: • Acute MI, • Heart failure with scar or hibernating myocardium, • Chronic ischemia not amenable to conventional revascularization

  7. Delivery options for stem cells • Intracoronary Coronary sinus • Direct myocardial injection epicardial, endocardial), • Intravenous • Bone marrow mobilization Delivery devices

  8. Human studies with cell therapy in cardiovascular diseases • Cell types: • Endothelial progenitor cells: • Bone marrow mononuclear cells, • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc • Peripheral blood progenitors (ex vivo expansion) • Cord blood • Skeletal myoblasts • Mesenchymal stem cells • Resident cardiac stem cells • Disease states: • Acute MI, • Heart failure with scar or hibernating myocardium, • Chronic ischemia not amenable to conventional revascularization

  9. Skeletal myoblasts • Myoblasts derived from satellite cells in skeletal muscle • With appropriate stimulus, satellite cells differentiate into muscle fibres • Highly resistant to ischemia • Do not contract spontaneously • Do not differentiate into cardiomyocytes • Orient towards cardiac stress reducing thinning and dilation • Improve diastolic and systolic function Potential risk of fatal arrhythmia;

  10. Human studies with cell therapy in cardiovascular diseases • Cell types: • Endothelial progenitor cells: • Bone marrow mononuclear cells, • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc • Peripheral blood progenitors (ex vivo expansion) • Cord blood • Skeletal myoblasts • Mesenchymal stem cells • Resident cardiac stem cells • Adipose tissue progenitors • Disease states: • Acute MI, • Heart failure with scar or hibernating myocardium, • Chronic ischemia not amenable to conventional revascularization

  11. Allogeneic Mesenchymal Stem Cells forAcute Myocardial Infarction • 60 patients enrolled • Baseline EF~50% • Intravenous adult human MSCs (Provacel™, Osiris Therapeutics) given 1-10 days after infarct (vs. placebo) • No increase in adverse events • No difference in baseline EF • LAD infarcts: • MSC therapy: increase in EF at 3 (48.8 ± 11.9 vs 57.1 ± 8.2; P 0.02) and and 6 months (56.3 ± 8.7; P=0.05). • Changes in EF in the placebo patients and the non-LAD groups were not significant Hare JM, et al., ACC Scientific Sessions 2007 (abstract) Zambrano, T, et al., Circulation. 2007;116:II_202. (abstract)

  12. Human studies with cell therapy in cardiovascular diseases • Cell types: • Endothelial progenitor cells: • Bone marrow mononuclear cells, • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc • Peripheral blood progenitors (ex vivo expansion) • Cord blood • Skeletal myoblasts • Mesenchymal stem cells • Resident cardiac stem cells • Disease states: • Acute MI, • Heart failure with scar or hibernating myocardium, • Chronic ischemia not amenable to conventional revascularization

  13. Human studies with cell therapy in cardiovascular diseases • Cell types: • Endothelial progenitor cells: • Bone marrow mononuclear cells, • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc • Peripheral blood progenitors (ex vivo expansion) • Cord blood • Skeletal myoblasts • Mesenchymal stem cells • Resident cardiac stem cells • Disease states: • Acute MI, • Heart failure with scar or hibernating myocardium, • Chronic ischemia not amenable to conventional revascularization

  14. Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure Biosense Webster Myostar/ NOGA catheter Perrin E Circulation 2003

  15. Losordo D et al ACC 2009

  16. Losordo D et al ACC 2009

  17. Clinical trials with endothelial progenitor cells Disease states: • Acute MI, • Heart failure with hibernating myocardium • Myocardial ischemia and unrevascularizable disease • Peripheral arterial disease

  18. Transdifferentiation to cardiomyocytes Attenuation of Remodelling Arteriogenesis or Angiogenesis Paracrine effects Cell fusion Reduction of apoptosis Promoting endogenous Cardiac stem cell function Potential mechanisms of benefit of bone marrow derived cells after myocardial infarction

  19. Improvement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow-derived cells (BMCs) • More than 1200 patients with STEMI randomized • Modest improvement in ejection fraction (EF 3%) • Reduction in infarct size • Reduction in end-systolic volume • Comparison with pharmacological therapy post MI: • Capricorn study (Carvedilol vs. placebo after AMI EF<40%): EF increased by 3.9% and end-systolic volume by 9.2 mls. Mortality reduced by 25%. Enca Martin-Rendon Eur Heart J 2008; 29:1807 Abdel-Latif, A. et al. Arch Intern Med 2007;167:989-997 . Lipinski et al J Am Coll Cardiol; 2007;50:1761

  20. Bone marrow CD34+ cell injection after STEMI (AMRS 1) Emory University, Atlanta, GA ; Vanderbilt University, Nashville, TN; Lindner Center, Cincinnatti, Ohio; Texas Heart Institute Primary Objective Feasibility and safety of intra-coronary infusion of autologous CD34+ cells at three dose levels (5, 10, 15 million). Secondary Objective To assess the effect on cardiac function (MRI, echo) and infarct region perfusion (SPECT) . Assess mobility/homing (CXCR-4), viability and in vitro hematopoietic and precursor cell growth (CFU-G). Only study to investigate cell dose-response Largest dose of i.c. CD34+ cells given to date

  21. Day 1-9 Bone marrow harvest SPECT MRI Screening Echo Stenting + Usual medical Rx EF <50% Intracoronary cell product infusion Days 1-10 Chest pain + STEMI cell product Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI Cell product concentration

  22. Progenitor cell Therapeutics, NJ Sterility Pyrogenicity Ex vivo viability ISOLEX is a trademark of Baxter International Inc.

  23. Paramagnetic bead Anti-CD34 mAb S S S S S S S S S S S S S S S S S S S S S Magnet MNC Fraction Containing CD34+ Stem Cells SAM Ig antibody PR34+ Release Agent Purified CD34+ Cells Paramagnetic CD34 Positive Cell Selection

  24. Volume reduction of CD34+ selected cells

  25. Intracoronary cell therapy trial :bone marrow CD34+ cell injection post acute ST elevation MI (AMR 1) CD34+ cells are infused via the infarct related artery 6 to 9 days following successful coronary artery stenting.

  26. Day 1-9 Bone marrow harvest SPECT MRI Screening Echo Stenting + Usual medical Rx EF <50% Intracoronary cell product infusion Days 1-10 Chest pain + STEMI cell product Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI Cell product concentration

  27. Bone marrow CD34+ cell injection after STEMI (AMRS 1) -5.7 mL vs. -0.1 mL +4%vs.+1% -10% vs. -3%

  28. Bone marrow CD34+ cell injection after STEMI (AMRS 1) Resting perfusion: SPECT total severity score Resting total severity score Control, 5 million cells = +13 10, 15 million cells = -256 (p=0.01)

  29. Bone marrow CD34+ cell injection after STEMI (AMRS 1) Intracoronary infusion of autologous bone marrow CD34+ cells during the repair phase after STEMI at higher doses than previously administered is safe, and may be associated with improved functional recovery from enhanced perfusion to the peri-infarct zone.

  30. Bone marrow-derived cell therapy for AMI • Ongoing studies: www.clinicaltrials.org • Worldwide: Ten studies • US: Bone marrow: Intracoronary administration • TIME (n=120), (NHLBI), • Late –TIME (n=87) (NHLBI), • Minneapolis (n=60) • CD34+ cells: AMRS (Amorcyte) • Allogeneic Mesenchymal Precursor Cells n=25 Direct myocardial injection (Angioblast Systems) • Mesenchymal Stem Cells (Provacel) Intravenous injection (Osiris)

  31. Cell therapy trials in acute MI Progenitor Cell Laboratory W. Robert Taylor M.D., PhD Diane Sutcliffe AMRS1 Sponsor: Amorcyte Inc. PI: Arshed Quyyumi MD Clinical sites: Emory University, Atlanta, GA Vanderbilt University, TN Douglas Vaughan MD Lindner Center, Ohio Dean Keriakis MD Texas Heart Institute Jim Willerson MD Core labs: Fabio Esteves MD James Galt PhD Stam Lerakis MD John Oshinski PhD Quyyumi Lab: Jonathan Murrow M.D. Mick Ozkor MD. Saurabh Dhawan M.D. Riyaz Patel M.D. Ayaz Rehman MD A. Konstantinos M.D. Salman Sher Yusuf Ahmed Irina Uphoff Ibhar Al-Mheid Nino Kavtaratze Hamid Syed Shawn Arshad Hematology/ Stem Cell Processing E. Waller M.D., PhD Sagar Lonial M.D. Kreton Mavromatis M.D. Ziyad Ghazzal M.D. Habib Samady M.D. Tanveer rab MD. Chandan Devireddy MD Henry Liberman MD Douglas Morris MD Emory Intereventional faculty

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